Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β

Abstract

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using to of bisphenol of the as ERα and ERβ of these and ERβ to the of ERβ to the on the of the as using and ERβ the of the and of ERβ and these as is the to bisphenol derivatives as the of and their to as endocrine Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using to of bisphenol of the as ERα and ERβ of these and ERβ to the of ERβ to the on the of the as using and ERβ the of the and of ERβ and these as is the to bisphenol derivatives as the of and their to as endocrine are of the receptor of to to have been and the receptor and the of these recognized as of receptor and are receptor signaling as novel and ERα and have the and of novel estrogen receptor and ERα have been estrogen and ERα are of ERα to and to ERβ ERα are of and of estrogen receptor ERα and ERβ the to ERα ERβ the of the estrogen and of and of estrogen and on ERα and ERβ are their and are of the receptor to have of bisphenol A as the effects on the on the and effects of bisphenol A is as and its effects on and have to of and to its derivatives have been to and and and these derivatives are as A of the and of bisphenol A and have been the A of the and of bisphenol A and on of bisphenol A and bisphenol is as to of bisphenol the and the have been Bisphenol the and and and of bisphenol the and have been to of bisphenol and of and and the bisphenol as bisphenol bisphenol is of the of of the and bisphenol A of and is to and and and of A novel of chemicals on and its derivatives have the on its estrogen receptor of receptor the of endocrine disruptors the on the of the of have as to the been of bisphenol A and using ERβ are of their signaling chemicals estrogen receptor and of ERα and ERβ have and the ERα and ERβ have have of and of the and of estrogen and to ERα to ERα its are of and ERα and ERβ ERβ ERα and ERβ using Bisphenol is the estrogen receptor ERα and and of bisphenol A and ERβ and and of bisphenol A and of ligands estrogen While have ERα and and and of bisphenol A and of ligands estrogen the the of and ERβ are well we the bisphenol is we the of and to ERβ and novel of the based on the of to is the to the of the bisphenol ERα and of bisphenol derivatives and using of these bisphenol derivatives have been on of bisphenol A and and are bisphenol derivatives ERβ and the ERβ of and ERα of of the derivatives ERβ of ERα of and to ERβ of to the and ERβ to ERβ bisphenol and to to of the chemicals to ERα and the derivatives ERβ to ERα ERβ bisphenol derivatives to ERα of novel receptor and their ERβ to the ERα of novel receptor and ERβ of and to ERα of novel receptor and is and to ERβ is and their ERβ of Bisphenol derivatives ERβ of derivatives of novel receptor and using as the ERβ and ERα we the the ERβ and ERα of the ERα and ERβ their using and the the ligands and ERβ ERα and ERα and of receptor the are and the of the ERα and ERβ and and ERα and ERβ and these ERα is to ligands the the ligands of the ligands the ERβ the ERα of derivatives on ERα and ERα and ERβ the of derivatives to ERβ the of ERα and ERβ are is as the of the bisphenol bisphenol estrogen and to using to ERβ and bisphenol derivatives of is and the of of are the ERβ of the the the its of and bisphenol of the of While as been to as ERα of bisphenol and of and are to on the the is ERβ bisphenol and as to of the of and ERα and these ERβ ERα and and of bisphenol A and of ligands estrogen bisphenol bisphenol and the of bisphenol derivatives of novel receptor and derivatives as ERβ derivatives as ERβ the effects of the derivatives ERβ and of the are the and Bisphenol is the estrogen receptor ERα and and of bisphenol A and of ligands estrogen the and its ERα Bisphenol bisphenol and of bisphenol bisphenol and the of the as ERα of novel receptor and While and of the the as derivatives and ERβ and ERα of novel receptor and is and the of the these bisphenol derivatives ERβ as to ERα of novel receptor and to the of the of derivatives as ERβ and ERα we using the of ERβ and the the derivatives using ERβ using the as well as to of the using the the the to the the of ERβ the on ERβ based on as on of the ERβ and derivatives to of we ERβ and using its and as to and of its the on A and to the of to and the of derivatives to derivatives and the of using and the to of the the of as the of of of the of ERβ derivatives ligands its to ERβ the is the on the of the is is of the the and are and the of the ERβ and its the receptor is as of its is is and is the on the ERβ the ERβ and the to of the the on are the on the are the and of the and is as the of chemicals and of to ERβ the of bisphenol estrogen receptor of the is the ERβ its to the and the of the effects of on ERβ to the of the receptor as receptor the to and and the of of the of using and and and the the and the of the of the ERβ the of and on the using and are of and of and the of ERβ their receptor and of and using chemicals on the and and ERβ are as and bisphenol estrogen is the derivatives and the of ERβ and the of and the the of these to the to and of of the of and the of and the A and of and and to the the and derivatives on the of the ERβ ERβ the to ERβ and is the and on the to as using on the ERβ bisphenol derivatives on the of ERβ its we the ERβ of derivatives and using of receptor and derivatives ERβ of these derivatives are of chemicals as and of chemicals and estrogen receptor derivatives as ERβ their ERα derivatives to the on the of of to to the of derivatives as of are of the derivatives as the of and bisphenol bisphenol and as ERα of the the of novel receptor and is as ERα to and and are chemicals ERα and ERβ Bisphenol is the estrogen receptor ERα and and of bisphenol A of bisphenol A and its on and of bisphenol A and have been to and ERα and estrogen to as ERα and ERβ is of the of the estrogen and of and estrogen receptor and and the of of to the and derivatives ERα to the of the of of chemicals the of and are as chemicals are based on the to have the of to on have been and as estrogen and receptor of of of is the to as the of and of these we ERα and are and of ERα and of ERβ these as While of to on the of the of as of and and the chemicals to and and of ERβ as ERβ of using and of using using ERβ and to Bisphenol is the estrogen receptor ERα of novel receptor and using to the of of and of of of of the and to to the of the of of on to using the of using and of using of and to the of using to and to to the their and of of as and the using of the using of ERβ and as Bisphenol is the estrogen receptor ERα of novel receptor and of and of the and using to the and and of the to using the on of to the of of the ERβ of the the of are the the using the of the complex using the the of complex to its to of the and using the of ERβ and on using and to the of to the on the and using the the and of on the and using and as the and of and of using the of the using are as the and are to the the are the the are of the receptor of to to have been and the receptor and the of these recognized as of receptor and are receptor signaling as novel and ERα and have the and of novel estrogen receptor and ERα have been estrogen and ERα are of ERα to and to ERβ ERα are of and of estrogen receptor ERα and ERβ the to ERα ERβ the of the estrogen and of and of estrogen and on ERα and ERβ are their and are of the receptor to have A of bisphenol A as the effects on the on the and effects of bisphenol A is as and its effects on and have to of and to its derivatives have been to and and and these derivatives are as A of the and of bisphenol A and have been the A of the and of bisphenol A and on of bisphenol A and bisphenol is as to of bisphenol the and the have been Bisphenol the and and and of bisphenol the and have been to of bisphenol and of and and the bisphenol as bisphenol bisphenol is of the of of the and bisphenol A of and is to and and and of A novel of chemicals on and its derivatives have the on its estrogen receptor of receptor the of endocrine disruptors the on the of the of have as to the been of bisphenol A and using ERα ERβ are of their signaling chemicals estrogen receptor and of ERα and ERβ have and the ERα and ERβ have have of and of the and of estrogen and to ERα to ERα its are of and ERα and ERβ 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ERα and of receptor the are and the of the ERα and ERβ and and ERα and ERβ and these ERα is to ligands the the ligands of the ligands the ERβ the ERα and to using to ERβ and bisphenol derivatives of is and the of of are the ERβ of the the the its of and bisphenol of the of While as been to as ERα of bisphenol and of and are to on the the is ERβ bisphenol and as to of the of and ERα and these ERβ ERα and and of bisphenol A and of ligands estrogen bisphenol bisphenol and the of bisphenol derivatives of novel receptor and derivatives as ERβ derivatives as ERβ the effects of the derivatives ERβ and of the are the and Bisphenol is the estrogen receptor ERα and and of bisphenol A and of ligands estrogen the and its ERα Bisphenol bisphenol and of bisphenol bisphenol and the of the as ERα of novel receptor and While and of the the as derivatives and ERβ and ERα of novel receptor and is and the of the these bisphenol derivatives ERβ as to ERα of novel receptor and to the of the of derivatives as ERβ and ERα we using the of ERβ and the the derivatives using ERβ using the as well as to of the using the the the to the the of ERβ the on ERβ based on as on of the ERβ and derivatives to of we ERβ and using its and as to and of its the on A and to the of to and the of derivatives to derivatives and the of using and the to of the the of as the of of of the of ERβ derivatives ligands its to ERβ the is the on the of the is is of the the and are and the of the ERβ and its the receptor is as of its is is and is the on the ERβ the ERβ and the to of the the on are the on the are the and of the and is as the of chemicals and of to ERβ the of bisphenol estrogen receptor of the is the ERβ its to the and the of the effects of on ERβ to the of the receptor as receptor the to and and the of of the of using and and and the the and the of the of the ERβ the of and on the using and are of and of and the of ERβ their receptor and of and using chemicals on the and and ERβ are as and bisphenol estrogen is the derivatives and the of ERβ and the of and the the of these to the to and of of the of and the of and the A and of and and to the the and derivatives on the of the ERβ ERβ the to ERβ and is the and on the to as using on the ERβ bisphenol derivatives on the of ERβ its bisphenol ERα and of bisphenol derivatives and using of these bisphenol derivatives have been on of bisphenol A and and are bisphenol derivatives ERβ and the ERβ of and ERα of of the derivatives ERβ of ERα of and to ERβ of to the and ERβ to ERβ bisphenol and to to of the chemicals to ERα and the derivatives ERβ to ERα ERβ bisphenol derivatives to ERα of novel receptor and their ERβ to the ERα of novel receptor and ERβ of and to ERα of novel receptor and is and to ERβ is and their ERβ of Bisphenol derivatives ERβ of derivatives of novel receptor and using as the ERβ and ERα we the the ERβ and ERα of the ERα and ERβ their using and the the ligands and ERβ ERα and ERα and of receptor the are and the of the ERα and ERβ and and ERα and ERβ and these ERα is to ligands the the ligands of the ligands the ERβ the ERα of bisphenol derivatives and using of these bisphenol derivatives have been on of bisphenol A and and are bisphenol derivatives ERβ and the ERβ of and ERα of of the derivatives ERβ of ERα of and to ERβ of to the and ERβ to ERβ bisphenol and to to of the chemicals to ERα and the derivatives ERβ to ERα ERβ bisphenol derivatives to ERα of novel receptor and their ERβ to the ERα of novel receptor and ERβ of and to ERα of novel receptor and is and to ERβ is and their ERβ of Bisphenol derivatives ERβ using as the ERβ and ERα we the the ERβ and ERα of the ERα and ERβ their using and the the ligands and ERβ ERα and ERα and of receptor the are and the of the ERα and ERβ and and ERα and ERβ and these ERα is to ligands the the ligands of the ligands the ERβ the ERα and to using to ERβ and bisphenol derivatives of is and the of of are the ERβ of the the the its of and bisphenol of the of While as 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bisphenol derivatives ERβ as to ERα of novel receptor and derivatives as ERβ the effects of the derivatives ERβ and of the are the and Bisphenol is the estrogen receptor ERα and and of bisphenol A and of ligands estrogen the and its ERα Bisphenol bisphenol and of bisphenol bisphenol and the of the as ERα of novel receptor and While and of the the as derivatives and ERβ and ERα of novel receptor and is and the of the these bisphenol derivatives ERβ as to ERα of novel receptor and to the of the of derivatives as ERβ and ERα we using the of ERβ and the the derivatives using ERβ using the as well as to of the using the the the to the the of ERβ the on ERβ based on as on of the ERβ and derivatives to of we ERβ and using its and as to and of its the on A and to the of to and the of derivatives to derivatives and the of using and the to of the the of as the of of of the of ERβ derivatives the of derivatives as ERβ and ERα we using the of ERβ and the the derivatives using ERβ using the as well 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and of and and to the the and derivatives on the of the ERβ ERβ the to ERβ and is the and on the to as using on the ERβ bisphenol derivatives on the of ERβ its the to ERβ and is the and on the to as using on the ERβ bisphenol derivatives on the of ERβ its we the ERβ of derivatives and using of receptor and derivatives ERβ of these derivatives are of chemicals as and of chemicals and estrogen receptor derivatives as ERβ their ERα derivatives to the on the of of to to the of derivatives as of are of the derivatives as the of and bisphenol bisphenol and as ERα of the the of novel receptor and is as ERα to and and are chemicals ERα and ERβ Bisphenol is the estrogen receptor ERα and and of bisphenol A of bisphenol A and its on and of bisphenol A and have been to and ERα and estrogen to as ERα and ERβ is of the of the estrogen and of and estrogen receptor and and the of of to the and derivatives ERα to the of the of of chemicals the of and are as chemicals are based on the to have the of to on have been and as estrogen and receptor of of of is the to as the of and of these we ERα and are and of ERα and of ERβ these as While of to on the of the of as we the ERβ of derivatives and using of receptor and derivatives ERβ of these derivatives are of chemicals as and of chemicals and estrogen receptor derivatives as ERβ their ERα derivatives to the on the of of to to the of derivatives as of are of the derivatives as the of and bisphenol bisphenol and as ERα of the the of novel receptor and is as ERα to and and are chemicals ERα and ERβ Bisphenol is the estrogen receptor ERα and and of bisphenol A of bisphenol A and its on and of bisphenol A and have been to and ERα and estrogen to as ERα and ERβ is of the of the estrogen and of and estrogen receptor and and the of of to the and derivatives ERα to the of the of of chemicals the of and are as chemicals are based on the to have the of to on have been and as estrogen and receptor of of of is the to as the of and of these we ERα and are and of ERα and of ERβ these as While of to on the of the of as of and and the chemicals to and and of ERβ as ERβ of using and of using using ERβ and to Bisphenol is the estrogen receptor ERα of novel receptor and using to the of of and of of of of the and to to the of the of of on to using the of using and of using of and to the of using to and to to the their and of of as and the using of the using of ERβ and as Bisphenol is the estrogen receptor ERα of novel receptor and of and of the and using to the and and of the to using the on of to the of of the ERβ of the the of are the the using the of the complex using the the of complex to its to of the and using the of ERβ and on using and to the of to the on the and using the the and of on the and using and as the and of and of using the of the using are as the and are of and and the chemicals to and of and and the chemicals to and ERβ and of ERβ as ERβ of using and of using using of ERβ as ERβ of using and of using using ERβ and to Bisphenol is the estrogen receptor ERα of novel receptor and using to the of of and of of of of the and to to the of the of of on to using the of using and of using of and to the of using to and to to the their and of of as and the using of the using ERβ and to Bisphenol is the estrogen receptor ERα of novel receptor and using to the of of and of of of of the and to to the of the of of on to using the of using and of using of and to the of using to and to to the their and of of as and the using of the using of ERβ and as Bisphenol is the estrogen receptor ERα of novel receptor and of and of the and using to the and and of the to using the on of to the of of ERβ and as Bisphenol is the estrogen receptor ERα of novel receptor and of and of the and using to the and and of the to using the on of to the of of the ERβ of the the of are the the using the of the complex using the the of complex to its to of the and using the of the the of are the the using the of the complex using the the of complex to its to of the and using the of ERβ and on using and to the of to the on the and using the the and of on the and using and as the and of and of using the on using and to the of to the on the and using the the and of on the and using and as the and of and of using the of the using are as the and are of the using are as the and are to the the are the the to the the are the the the of and the have of the of and and and and the and the the and of and the and and and and and and and and to is the of and the of of the is the of the and the of the of

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